BACKGROUND: RET fusions are present in 1%-2% of non-small cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naïve patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once-daily (QD) until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 06 November 2020 (data cutoff), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% (54/75; 95% CI, 60-82) for treatment-naïve patients and 59% (80/136; 95% CI, 50-67) for patients with prior platinum-based chemotherapy (enrolment cutoff for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naïve patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naïve patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI, 35-93); all had received prior systemic treatment. In treatment-naïve patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cutoff (n = 116), the most common Grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naïve patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.
- Griesinger, F.
- Curigliano, G.
- Thomas, M.
- Subbiah, V.
- Baik, C. S.
- Tan, D. S. W.
- Lee, D. H.
- Misch, D.
- Garralda, E.
- Kim, D. W.
- van der Wekken, A. J.
- Gainor, J. F.
- Paz-Ares, L.
- Liu, S. V.
- Kalemkerian, G. P.
- Houvras, Y.
- Bowles, D. W.
- Mansfield, A. S.
- Lin, J. J.
- Smoljanovic, V.
- Rahman, A.
- Kong, S.
- Zalutskaya, A.
- Louie-Gao, M.
- Boral, A. L.
- Mazieres, J.
Keywords
- *RET fusion
- *RET inhibition
- *frontline therapy
- *non-small cell lung cancer
- *pralsetinib
- *targeted therapy